The putative role of the hormone-sensitive lipase gene in the pathogenesis of Type II diabetes mellitus and abdominal obesity

Klannemark, Mia; Orho, M.; Langin, Dominique; Laurell, Henrik; Holm, Cecilia; Reynisdottir, Signy; Arner, Peter; Groop, Leif

doi:10.1007/s001250051099

Cited by 78 publications

(68 citation statements)

References 22 publications

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“…This is further supported by the finding that when expressed, the mutation is associated with impaired catecholaminestimulated lipolysis [71,72]. In addition, a variant in the gene for hormone sensitive lipase was more often transmitted from heterozygous diabetic parents to the abdominal obese offspring [73]. This variant was particularly common in Type II diabetic patients with a high WHR.…”

Section: Discussionmentioning

confidence: 83%

Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins

et al. 2000

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There is plenty of evidence that Type II (non-insulindependent) diabetes mellitusis a disease with a strong genetic predisposition [1±3]. In Finland, the estimated lifetime relative risk (l) of developing diabetes for a sibling to a person with Type II diabetes is about three [4]. This value decreases with age suggesting that environmental factors become more important with increasing age. Obesity and physical inactivity are the most important triggers of the disease. Several twin studies have provided unequivocal support for the genetic nature of the adult-onset type of diabetes, i. Abstract Aims/hypothesis. To estimate the heritability of insulin sensitivity and insulin secretion, both of which are considered to contribute to the development of Type II (non-insulin-dependent) diabetes mellitus. Methods. Intraclass correlation coefficients and heritability estimates for insulin sensitivity (euglycaemic clamp) as well as first-phase and late-phase insulin secretion (intravenous glucose tolerance test) were calculated in 21 monozygotic and 20 dizygotic twin pairs of the same sex between 54 and 72 years of age. Results. Intrapair correlations for all traits were consistently higher in monozygotic than in dizygotic pairs. Insulin secretion correlated significantly only between monozygotic (first-phase r = 0.55; p = 0.003 and late-phase r = 0.66; p < 0.001) twins giving heritability estimates of 0.55 and 0.58, respectively. Insulinstimulated glucose uptake showed a more modest correlation between monozygotic twins (r = 0.46; p = 0.015). The heritability estimate was 0.37. The heritability estimate for waist-to-hip ratio was 0.76 in female and 0.70 in male twins. Conclusion/interpretation. Genetic variability seems to contribute to the variance of insulin sensitivity as well as of insulin secretion. In the current study, genetic variance accounted almost 60 % for the variance in glucose-stimulated insulin secretion and almost 40 % for the variance in insulin-stimulated glucose uptake. Our data is also compatible with findings in monogenic forms of diabetes in which genetic defects in insulin secretion play a predominant part in the pathogenesis of hyperglycaemia. [Diabetologia (2000) Corresponding author: M. Lehtovirta, Helsinki University Central Hospital, Department of Medicine, Division of Internal Medicine, PO Box 346, FIN-00 029 HYKS, Finland Abbreviations: MZ, Monozygotic; DZ, dizygotic; MODY, maturity-onset diabetes of the young; WHR, waist-to-hip ratio; FFM, fat-free mass; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPI, first-phase insulin secretion in IVGTT; LPI, late-phase insulin secretion in IVGTT; Intraclass r, intraclass correlation coefficient; h 2 , heritability; A, additive component of variance; C, variance component due to shared environment; D, variance component due to dominance; E, variance component due to non-shared environmental influences.

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Section: Discussionmentioning

confidence: 83%

Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins

et al. 2000

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“…31 Two recent association studies showed some evidence that LIPE could represent a susceptibility gene for obesity and type 2 diabetes. 13,16 As proposed by Jiang et al, 32 black adolescent women have greater levels of insulin than their white counterparts, suggesting that they are more prone to develop insulin resistance. This result was also observed in the HERITAGE cohort with adult black women exhibiting greater levels of insulin than white women.…”

Section: Discussionmentioning

confidence: 93%

“…11 An association was also found between a dinucleotide repeat in intron 7 of the LIPE gene 12 and type 2 diabetes in subjects with abdominal obesity. 13 Results from two studies revealed no evidence of linkage between the same dinucleotide repeat and familial combined hyperlipidemia in Finnish families 14 or atherogenic lipoprotein phenotype in dizygotic female twins. 15 Magre et al reported that the HSLi6(CA) n repeat polymorphism was associated with type 2 diabetes and obesity.…”

Section: Introductionmentioning

confidence: 98%

The hormone-sensitive lipase gene and body composition: the HERITAGE Family Study

et al. 2002

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OBJECTIVE:To investigate whether the C-60G polymorphism and other markers in the hormone-sensitive lipase (LIPE) gene are associated with baseline body composition and free-fatty acid (FFA) concentrations measured at rest and during low-intensity exercise in white and black subjects participating in the HERITAGE Family Study. SUBJECTS: Adult sedentary white (245 men and 258 women) and black (91 men and 185 women) subjects. MEASUREMENTS: body mass index (BMI); fat mass (FAT); percentage body fat (%FAT); fat-free mass (FATFR); sum of eight skinfolds (SF8); subcutaneous (ASF), visceral (AVF) and total (ATF) abdominal fat areas assessed by CT scan; plasma FFA concentrations measured at rest (FFAR), at a power output of 50 W (FFA50) and at a relative power output of 60% of VO 2max (FFA60%); and fasting insulin (INS). STATISTICAL ANALYSIS: Association between the C-60G polymorphism of the LIPE gene and each phenotype was tested separately in men and women using ANCOVA with the effects of age and race as covariates and with further adjustment for FAT for ASF, AVF, ATF, FFAR, FFA50 and FFA60%. Secondly, owing to significant gene-by-race interaction, associations were investigated separately in each of the two race groups. Linkage was tested with the C-60G polymorphism, a dinucleotide repeat polymorphism in the intron 7 of the LIPE gene and two microsatellites markers (D19S178 and D19S903) flanking the LIPE gene. RESULTS: There were no race differences in the allele frequencies of the C-60G polymorphism of the LIPE gene. No association or gene-by-race interaction was observed in men. However, in women, strong gene-by-race interactions were observed for BMI (P ¼ 0.0005), FAT (P ¼ 0.0007), %FAT (P ¼ 0.0003), SF8 (P ¼ 0.0001), ASF (P ¼ 0.03) and ATF (P ¼ 0.01). When the analysis was performed separately in each race, white women carriers of the -60G allele exhibited lower %FAT (P ¼ 0.005) and SF8 (P ¼ 0.01) than non-carriers, while in black women, the -60G allele was associated with higher BMI (P ¼ 0.004), FAT (P ¼ 0.009), %FAT (P ¼ 0.01) and SF8 (P ¼ 0.0009). These associations were no longer significant after adjusting for INS. Evidence of linkage was observed in whites with ATF, FFAR, FFA50 and FFA60%. CONCLUSION: These results suggest that the C-60G polymorphism in the LIPE gene plays a role in determining body composition and that its effect is sex-, race-and insulin-dependent.

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“…A non-coding dinucleotide repeat and other forms of genetic variability, which are detected by restriction-length fragment polymorphism, associate with obesity in different populations. 19,20 It remains to be established if structural variants in the hormone sensitive lipase gene also alter protein expression or enzyme function. The detected polymorphisms in hormone sensitive lipase could also re¯ect more important variations on genes near the hormone sensitive lipase locus.…”

Section: Hormone Sensitive Lipasementioning

confidence: 99%

Hunting for human obesity genes? Look in the adipose tissue!

Arner

2000

Int J Obes

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The putative role of the hormone-sensitive lipase gene in the pathogenesis of Type II diabetes mellitus and abdominal obesity

Cited by 78 publications

References 22 publications

Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins

Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins

The hormone-sensitive lipase gene and body composition: the HERITAGE Family Study

Hunting for human obesity genes? Look in the adipose tissue!

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